Allergic asthma is a highly prevalent chronic respiratory disease whose symptoms respond to treatment with corticosteroids and 2-gonists but no curative intervention has been developed. The disease is characterized by bronchial inflammation and airway hyperreactivity (AHR) to a variety of environmental stimuli including allergens. The hallmarks of allergic asthma include infiltration of the airways by CD4+ Th2 cells and eosinophils, airway remodeling, and increased mucus secretion. In seeking new therapeutic strategy for limiting allergic lung inflammation, CB2 selective agonists were designed and formulated so that they can be delivered intranasally to mice. Our preliminary work using a mouse model of asthma showed that administration of a CB2 selective agonist was highly effective in abrogating allergic airway inflammation. Specifically, the CB2 agonist caused a marked inhibition in the accumulation of allergen- specific CD4+ T cells, eosinophils and CD11c+ dendritic cells into the airways following allergen inhalation. Little is known about the effects of cannabinoids on allergic inflammatory responses in the lung and the precise role of CB2 receptors in modulating allergic lung inflammation remains to be investigated. Our objectives are to refine methods for designing and delivering peripherally acting CB2 selective agonists and to determine the cellular mechanism of action of the CB2 selective agonists in the lung during allergic inflammation. Our preliminary work has enabled us to formulate the hypothesis that: the administration of peripherally acting CB2 selective agonists to the airways attenuates both allergic lung inflammation and the associated AHR by promoting the production of the anti-inflammatory cytokine IL-10. This hypothesis will be tested through the following two specific aims: (1) to optimize the localized action of CB2 selective agonists and determine their effect on allergic lung inflammation and the associated AHR, and (2) to investigate the cellular and molecular mechanism of CB2 agonist-mediated inhibition of allergic airway inflammation. Experiments are designed to define receptor specificity of action of these agents using both CB2-/- and CB1-/- mice. In addition, a novel fluorescent CB2 selective compound will be used to probe cellular expression of CB2 receptors during allergic inflammation. Successful completion of the work will provide a novel therapeutic approach for the treatment of asthma and improved understanding of the anti- inflammatory action of CB2 agonists in allergic lung inflammation. PUBLIC HEALTH RELEVANCE: This grant aims to investigate the mechanism of action of locally acting CB2 selective agonists and examine their potential as novel therapeutic agents to suppress allergic lung inflammation. Proposed experiments will vastly advance our understanding of the mode of action of this class of compounds on the inflammatory response in asthma and facilitate the development of new therapies.